Paclitaxel, a well known potent antitumor compound having a broad spectrum of antitumor activities, has the following structure of formula (I): ##STR1## Commercial pharmaceutical products containing this compound are available, e.g., for treating ovarian and breast cancer in women. For these reasons, greater and greater supplies of this compound are required each year. Paclitaxel and baccatine III are extracted with difficulty and in general in low yields from the trunk barks of different Taxus species. Thus, alternative sources of this compound are necessary.
Several synthetic methods have been reported both in scientific and patent literature. U.S. Pat. No. RE-34,227 (a reissue of U.S. Pat. No. 4,924,011) discloses the semisynthesis of paclitaxel using a 10-deacetyl-baccatine III derivative which is protected in the 7 position with a tri-alkyl-silyl group which is specifically shown as a tri-ethyl-silyl ("TES") group and which is also protected in the 10 position with an acetyl group. This baccatine III derivative is allowed to react with a (2R,3S)-N-benzoyl-2-O-(1-ethoxyethyl)-3-phenylisoserine compound before removal of the protecting groups to obtain the paclitaxel.
In PCT application WO-93/06094, paclitaxel was prepared by reacting a side chain precursor of a .beta.-lactam compound with 7-O-TES-baccatine III derivative to provide a 7-TES-baccatin III reaction product. After a mild acidic post-reaction treatment, paclitaxel was obtained.
In U.S. Pat. No. 5,476,954, the synthesis of paclitaxel was conducted starting from a protected 10-deacetyl-baccatine III derivative that contained a 2,2,2-tri-chloroethoxy-carbonyl ("TROC") protective group in both the 7 and 10 positions of the derivative.
It is well known that the key step in the semisynthesis of paclitaxel is to selectively protect the 7 position with a leaving group that can be easily removed. This is because the hydroxy group in that position of the taxane structure is much more reactive than those in position 10 or 13, and the paclitaxel product to be synthesized needs to have a hydroxy group in that position. Until now, however, the most useful protecting group was considered to be TES. The derivatization yield of 10-deacetyl-baccatine III with TES is typically about 85% when 20 moles of the reagent are used. The acetylation step, using 5 equivalents of acetylchloride, provides about 85% of 7-TES-baccatine III. as per the teachings of PCT application WO-93/06094 and its U.S. equivalent documents such as U.S. Pat. No. 5,574,156.
In view of the importance of paclitaxel, however, new and improved methods for its production are desirable. The present invention provides such improved syntheses of paclitaxel and its analogs primarily using new derivatives of 10-deacetyl-baccatin III as intermediates.